Abstract

The long-term objective of this research is to understand the molecular basis of ion selectivity and gating regulation in K+ channels. Potassium channels produce electrical signals in nerve cells, control the pace of the heart, and allow hormones to be secreted into the bloodstream. The first specific aim addresses the mechanism by which K+ channels discriminate between K+ and Na+ ions, a property essential to cell biology. Electrophysiology and x-ray crystallography techniques will be used to characterize ion coordination in the pore. The second specific aim seeks to understand the role of voltage dependent K+ channel Beta subunits in cell biology. These subunits attach to K+ channels at the cell membrane's inner surface and they have enzymatic potential. They are ubiquitous in the brain and have been implicated in the control of neural excitability and in sensing oxygen levels. Electrophysiology and x-ray techniques will be used to study Beta subunit function. The third specific aim focuses on a structural component of the HERG K+ channel that controls its gating. The HERG K+ channel governs electrical activity of the heart; its malfunction is a cause of sudden death by cardiac arrhythmia.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM047400-10
Application #
6386297
Study Section
Special Emphasis Panel (ZRG1-MDCN-3 (01))
Program Officer
Shapiro, Bert I
Project Start
1992-08-01
Project End
2004-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
10
Fiscal Year
2001
Total Cost
$248,830
Indirect Cost

  Institution

Name
Rockefeller University
Department
Biology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Valiyaveetil, Francis I; Sekedat, Matthew; Mackinnon, Roderick et al. (2004) Glycine as a D-amino acid surrogate in the K(+)-selectivity filter. Proc Natl Acad Sci U S A 101:17045-9
Zhou, Yufeng; MacKinnon, Roderick (2004) Ion binding affinity in the cavity of the KcsA potassium channel. Biochemistry 43:4978-82
Zhou, Ming; MacKinnon, Roderick (2004) A mutant KcsA K(+) channel with altered conduction properties and selectivity filter ion distribution. J Mol Biol 338:839-46
Zhou, Yufeng; MacKinnon, Roderick (2003) The occupancy of ions in the K+ selectivity filter: charge balance and coupling of ion binding to a protein conformational change underlie high conduction rates. J Mol Biol 333:965-75
Yifrach, Ofer; MacKinnon, Roderick (2002) Energetics of pore opening in a voltage-gated K(+) channel. Cell 111:231-9
Gulbis, J M; Zhou, M; Mann, S et al. (2000) Structure of the cytoplasmic beta subunit-T1 assembly of voltage-dependent K+ channels. Science 289:123-7
Jiang, Y; MacKinnon, R (2000) The barium site in a potassium channel by x-ray crystallography. J Gen Physiol 115:269-72
Morrill, J A; MacKinnon, R (1999) Isolation of a single carboxyl-carboxylate proton binding site in the pore of a cyclic nucleotide-gated channel. J Gen Physiol 114:71-83
Gulbis, J M; Mann, S; MacKinnon, R (1999) Structure of a voltage-dependent K+ channel beta subunit. Cell 97:943-52
Roux, B; MacKinnon, R (1999) The cavity and pore helices in the KcsA K+ channel: electrostatic stabilization of monovalent cations. Science 285:100-2

Showing the most recent 10 out of 20 publications